What medication is indicated for a 55-year-old female with a body mass index (BMI) of 23, a history of depression, currently on Prozac (fluoxetine), who has experienced increased depression and anxiety after stopping smoking 6 months ago?

Augment Fluoxetine with Bupropion

For this 55-year-old female with worsening depression and anxiety after smoking cessation 6 months ago, add bupropion (Wellbutrin SR) 150 mg twice daily to her existing Prozac regimen. This addresses both her treatment-resistant depression and the neurobiological changes from nicotine withdrawal that are likely contributing to her symptoms.

Rationale for Bupropion Augmentation

Augmenting SSRIs with bupropion is a well-established strategy for depression that has failed to respond adequately to SSRI monotherapy alone. 1 Low-quality evidence demonstrates that adding bupropion to SSRIs decreases depression severity more effectively than other augmentation strategies like buspirone. 1

The combination of fluoxetine and bupropion works through complementary mechanisms—fluoxetine affects serotonin pathways while bupropion works via noradrenergic and dopaminergic pathways. 1 This is particularly relevant for this patient because:

• Smoking cessation depletes dopamine and norepinephrine systems that nicotine previously stimulated, and bupropion directly addresses these deficits through its mechanism of action. 2, 3
• Bupropion has specific efficacy for both depression and nicotine withdrawal symptoms, making it uniquely suited for patients whose depression worsened after quitting smoking. 4, 2
• Past smoking history is associated with lower norepinephrine levels, which bupropion can help restore. 5

Specific Dosing Protocol

Start bupropion SR 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total). 1, 6 The second dose must be given before 3 PM to minimize insomnia risk. 1

• The maximum daily dose should not exceed 400 mg for SR formulation to maintain seizure risk at 0.1%. 1, 6
• With her BMI of 23, no dose adjustment is needed for weight considerations. 1

Critical Safety Screening Required

Before prescribing bupropion, verify the following absolute contraindications are absent: 4, 1, 6

• Seizure history or conditions predisposing to seizures (head trauma, brain metastases, CNS tumors)
• Current or prior eating disorder (bulimia or anorexia nervosa)—higher seizure incidence in these populations
• Uncontrolled hypertension—measure baseline blood pressure before starting
• Current MAOI use or within 14 days of discontinuation
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs

Monitoring Parameters

Assess patient status within 1-2 weeks of initiation for therapeutic response and adverse effects, particularly: 1, 6

• Neuropsychiatric symptoms: agitation, restlessness, unusual behavior changes, or suicidal thoughts (especially critical given FDA black box warning for patients under 24 years, though this patient is 55)
• Blood pressure and heart rate: monitor periodically, especially in first 12 weeks, as bupropion can elevate both 1, 6
• Anxiety levels: while bupropion treats depression, it has activating properties that could theoretically worsen anxiety initially 1

Allow 6-8 weeks at adequate dose before determining treatment response. 1, 6 If no adequate response occurs by this timeframe, modify the treatment approach.

Expected Benefits for This Patient

This combination offers several specific advantages: 1, 6

• Addresses post-cessation depression and anxiety: Bupropion has demonstrated efficacy for withdrawal symptoms including craving and anxiety that can persist months after quitting 4, 2
• Prevents relapse to smoking: The patient quit 6 months ago but remains at risk—bupropion reduces relapse risk even in former smokers 4, 2
• Lower sexual dysfunction risk: Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs, which may already be an issue with fluoxetine 6
• Weight neutral or weight loss: Unlike many antidepressants, bupropion is associated with minimal weight gain or even weight loss 1

Drug Interaction Considerations

The combination of fluoxetine and bupropion does not have significant pharmacokinetic interactions that would preclude their use together. 1 However, both medications can lower seizure threshold, making adherence to maximum dosing guidelines essential. The combined seizure risk remains approximately 0.1% (1 in 1,000) when bupropion is kept at or below 300 mg/day. 1

Common Side Effects to Counsel

The most common side effects include: 4, 1

• Disturbed sleep, dry mouth, headaches, and nausea
• Insomnia (administer second dose before 3 PM to minimize)
• Anxiety or nervousness initially (typically improves with continued use)

Why Not Other Options

Varenicline is contraindicated because this patient has active depression and anxiety—varenicline carries warnings about neuropsychiatric adverse effects including depressed mood and suicidal thoughts, requiring psychiatric history assessment before prescription. 4 While recent large trials (EAGLES) showed no significant increase in neuropsychiatric events, 4 the presence of current worsening depression makes bupropion the safer choice.

Nicotine replacement therapy (NRT) alone is insufficient because she quit 6 months ago—her issue is not acute nicotine withdrawal but persistent neurobiological changes and inadequate antidepressant response. 4, 2

Switching from fluoxetine to another antidepressant is less preferable than augmentation because it avoids SSRI discontinuation symptoms and the STAR*D trial showed augmentation with bupropion is equally effective as switching. 1